Comparison of the antinociceptive effect of acute morphine in female and male Sprague-Dawley rats using the long-lasting mu-antagonist methocinnamox

Male rats are more sensitive than female rats to the antinociceptive action of morphine. The present study used age-matched (9-10 weeks old) male and female Sprague-Dawley rats to investigate whether this difference is due to variation in mu-opioid receptor binding and G protein activation. In the warm-water tail-withdrawal assay at both 50 °C and 55 °C, morphine was 2-3 times more potent in males than females. In contrast, mu-opioid receptor number and the binding affinity of the mu-opioid agonists morphine and DAMGO in membranes from whole brain, cortex, thalamus, and spinal cord were not different between males and females. Similarly, morphine and DAMGO stimulation of G protein, determined using GTPase and [35S]GTPγS binding assays, did not show a difference between the sexes. The long-lasting mu-opioid receptor antagonist methocinnamox (0.32 mg/kg), given 24 h prior to morphine, reduced mu-opioid receptor number by approximately 50% in thalamic and spinal cord tissue from female and male rats and reduced the antinociceptive potency of morphine. Pretreatment of male rats with 0.32 mg/kg methocinnamox reduced the antinociceptive potency of morphine to that observed in female rats expressing a full complement of mu-opioid receptors. However, with increasing pretreatment doses of methocinnamox, the maximal antinociceptive effect of morphine was decreased in females but not males. The results suggest that pathways downstream of the mu-opioid receptor and G protein are more efficient in male rats than in female rats such that there is a larger receptor reserve for morphine-mediated antinociception.